G. La Rana

Acute Intracerebroventricular Administration of Palmitoylethanolamide, an Endogenous Peroxisome Proliferator-Activated Receptor-α Agonist, Modulates Carrageenan-Induced Paw Edema in Mice

Peroxisome proliferator-activated receptor (PPAR)-α is a nuclear transcription factor. Although the presence of this receptor in different areas of central nervous system (CNS) has been reported, its role remains unclear. Palmitoylethanolamide (PEA), a member of the fatty-acid ethanolamide family, acts peripherally as an endogenous PPAR-α ligand, exerting analgesic and anti-inflammatory effects. High levels of PEA in the CNS have been found, but the specific function of this lipid remains to be clarified. Using carrageenan-induced paw edema in mice, we show that i.c.v. administration of PEA may control peripheral inflammation through central PPAR-α activation. A single i.c.v. administration of 0.01 to 1 μg of PEA, 30 min before carrageenan injection, reduced edema formation in the mouse carrageenan test. This effect was mimicked by 0.01 to 1 μg of GW7647 [2-[[4-[2-[[(cyclohexylamino)carbonyl](4-cyclohexylbutyl)amino]ethyl]phenyl]thio]-2-methylpropanoic acid], a synthetic PPAR-α agonist. Moreover, central PEA administration significantly reduced the expression of the proinflammatory enzymes cyclooxygenase-2 and inducible nitric-oxide synthase, and it significantly restored carrageenan-induced PPAR-α reduction in the spinal cord. To investigate the mechanism by which i.c.v. PEA attenuated the development of carrageenan-induced paw edema, we evaluated inhibitor κB-α (IκB-α) degradation and nuclear factor-κB (NF-κB) p65 activation in the cytosolic or nuclear extracts from spinal cord tissue. PEA prevented IkB-α degradation and NF-κB nuclear translocation, confirming the involvement of this transcriptional factor in the control of peripheral inflammation. The obligatory role of PPAR-α in mediating the effects of PEA was confirmed by the lack of the compounds anti-inflammatory effects in mutant mice lacking PPAR-α. In conclusion, our data show for the first time that PPAR-α activation in the CNS can control peripheral inflammation.

Modulation of Neuropathic and Inflammatory Pain by the Endocannabinoid Transport Inhibitor AM404 [N-(4-Hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide]

The endocannabinoid system may serve important functions in the central and peripheral regulation of pain. In the present study, we investigated the effects of the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide] on rodent models of acute and persistent nociception (intraplantar formalin injection in the mouse), neuropathic pain (sciatic nerve ligation in the rat), and inflammatory pain (complete Freunds adjuvant injection in the rat). In the formalin model, administration of AM404 (1–10 mg/kg i.p.) elicited dose-dependent antinociceptive effects, which were prevented by the CB1 cannabinoid receptor antagonist rimonabant (SR141716A; 1 mg/kg i.p.) but not by the CB2 antagonist SR144528 (1 mg/kg i.p.) or the vanilloid antagonist capsazepine (30 mg/kg i.p.). Comparable effects were observed with UCM707 [N-(3-furylmethyl)-eicosa-5,8,11,14-tetraenamide], another anandamide transport inhibitor. In both the chronic constriction injury and complete Freunds adjuvant model, daily treatment with AM404 (1–10 mg/kg s.c.) for 14 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single administration of rimonabant (1 mg/kg i.p.) and was accompanied by decreased expression of cyclooxygenase-2 and inducible nitric-oxide synthase in the sciatic nerve. The results provide new evidence for a role of the endocannabinoid system in pain modulation and point to anandamide transport as a potential target for analgesic drug development.

AM404, an anandamide transport inhibitor, reduces plasma extravasation in a model of neuropathic pain in rat: Role for cannabinoid receptors

Neuropathic pain consequent to peripheral nerve injury has been associated with local inflammation. Following noxious stimulation afferent fibres release substance P (SP) and calcitonin-gene related peptide (CGRP), which are closely related to oedema formation and plasma leakage. The effect of the anandamide transport blocker AM404 has been studied on plasma extravasation after chronic constriction injury (CCI) which consists in a unilateral loose ligation of the rat sciatic nerve (Bennett and Xie, 1988). AM404 (1-3-10 mg kg(-1)) reduced plasma extravasation in the legated paw, measured as mug of Evans Blue per gram of fresh tissue. A strong effect on vascular permeability was also produced by the synthetic cannabinoid agonist WIN 55,212-2 (0.1-0.3-1 mg kg(-1)). Using specific antagonists or enzyme inhibitors, we demonstrate that cannabinoids act at several levels: data on the 3rd day suggest a strong involvement of substance P (SP) and calcitonin gene-related peptide (CGRP) in the control of vascular tone, whereas at the 7th and 14th days the major role seems to be played by prostaglandins (PGs) and nitric oxide (NO). Capsaicin injection in ligated paws of AM404- or WIN 55,212-2-treated rats resulted in an increase of Evans Blue extravasation, suggesting the involvement of the cannabinergic system in the protective effect of C fibres of ligated paws. Taken together, these data demonstrate the efficacy of cannabinoids in controlling pain behaviour through the modulation of several pain mediators and markers of vascular reactivity, such as SP, CGRP, PGs and NO.

Improvements in the in-beam γ-ray spectroscopy provided by an ancillary detector coupled to a Ge γ-spectrometer: the DIAMANT-EUROGAM II example

For the first time the 4π γ-ray spectrometer EUROGAM II has been coupled to a 4π light charged particle detector array, DIAMANT, during a test experiment on the reaction 32S + 58Ni at 120 MeV beam energy. A very large improvement in the peak-to-background ratio of the γ-spectra has been found when EUROGAM II is triggered by DIAMANT to select an exit channel. A simple algebra has been developed which provides theoretical estimates in good agreement with these experimental results. It is demonstrated that, depending on both the γ-spectrometer and ancillary detector performances, much better peak-to-background can be obtained by such a coupling. For the same peak-to-background ratio, the use of an ancillary detector allows for a lower γ-ray coincidence level and therefore improves the statistics. Ways to select the most appropriate ancillary detector are given. The ability of the ancillary detector to provide a total Doppler shift correction is crucial for the improvement of the peak-to-background ratio.

Investigation of the 40Ar + 197Au, 238U systems at 44 MeV/u

Abstract We have measured the angular correlation between two fragments emitted in the reactions Ar + Au and Ar + U at 44 MeV/u at GANIL. The aim was to investigate the amount of initial linear momentum transferred from the projectile to a fissioning nucleus. It turned out that this amount is much smaller than can be extrapolated from previous experiments. Furthermore, the probability of forming a fissioning nucleus is very small.

Linear momentum transfer investigated in the 20Ne + 197Au and 209Bi systems at 30 MeV/u

Abstract We have measured at SARA the correlation of fission fragments produced in the reactions 20 Ne + 197 Au and 20 Ne + 209 Bi at 30 MeV/u. The results show that the most probable amount of linear momentum transferred from the projectile to the fissioning nucleus is about 80 %. This corresponds to about 3.7 GeV/ c . The fission cross section is still rather large at this bombarding energy: 1.6±0.3 b for the Au target and 2.2±0.5 b for the Bi one. We present the results of a Monte-Carlo simulation which allows us to reproduce most of the experimental data under certain conditions which are discussed.

Emission of prompt nucleons in heavy ion collisions

We describe a simple dynamical model for the production of prompt nucleons at the very beginning of a heavy ion collision. Approximations often used in previous calculations (neglect of Pauli blocking, of window velocity and of its extension) have been checked. We apply the model to the calculation of prompt emitted neutrons in incomplete fusion reactions observed on the20Ne+165Ho system at 220, 402 and 700 MeV. Results of the model are extensively discussed.

Nuclear fragmentation processes in the 20Ne + 27Al system at 30 MeV/A

Abstract Inclusive energy spectra and angular distributions of Z ≦ 9 fragments from the Ne + AI reaction have been measured at 30 MeV/A. The spectra present three components. The high-energy component has a reduced momentum width σ0 of approximately 65 MeV/c, which is lower than the values observed in reactions induced by relativistic heavy ions. Conversely, for the low-energy component, the results are rather similar to high-energy heavy-ion data.

Pre-scission emission and evaporation residues survival probability in the reaction 37Cl + 120Sn at 187 MeV

Abstract Light particles spectra in coincidence with fission fragments have been measured for the reaction 187 MeV 37 Cl on 120 Sn populating 157 Ho compound nuclei at the excitation energy E x = 85 MeV. The experimental neutron pre-scission multiplicity for symmetric splintting is two times larger than the statistical model estimate. The experimental multiplicity is reproduced by calculations in which a fission delay, in agreement with systematics, is introduced. This empirical fission delay produces a sizeable increase, with respect to the standard statistical model estimate, of the survival probability against fission for nuclei with angular momentum around J ∼ h . The importance of this effect in the population of superdeformed and hyperdeformed structures in the evaporation residues is discussed.

Investigation of linear momentum transfer on the20NeJ197Au system at 30 MeV/A

We have deduced the linear momentum transferred from the projectile to the fissioning nucleus in the reaction20Ne+197Au at 30 MeV/A by measuring the folding angle between the two fission fragments. We found that the most probable linear momentum transfer represents 76% of the initial value.